Neurostimulation Comes of Age

Millions of people worldwide live active lives, thanks to implanted pacemakers that deliver electrical impulses to restore normal function to the heart. Now, electrical therapy of another sort — neurostimulation — could improve the quality of lives for patients with conditions ranging from chronic pain and epilepsy to deafness and morbid obesity.

The basic components of many of these systems are remarkably similar. Most feature an implanted pulse generator (IPG) connected to leads that carry an electrical stimulus to targeted nerves via carefully placed electrodes. A controller outside the body programs the implanted system for a stimulus regimen customized to the patient.

Until recent years, however, the number of patients helped by neurostimulation was relatively small versus alternate therapies, such as drugs and surgery. But advances in microprocessors, biocompatible materials, batteries, RF communications and software are now combining to produce much more effective systems, as well as easier to implant and, most important of all, more patient-friendly. At the same time, the medical world’s increased understanding of the nervous system, coupled with favorable results from actual treatment and clinical trials, have led more physicians to consider neurostimulation as a viable choice for their patients.

“There’s a growing realization that drugs can’t cure everyone and that they often produce harmful side-effects,” says James Cavuoto, a biomedical engineer and editor/publisher of Neurotech Reports, a monthly newsletter serving neurotechnology companies and the investment community. “So, clinicians are now more open to new treatment strategies.”

He adds, acceptance of neurotechnology devices also have benefited from favorable publicity, such as that surrounding radio personality Rush Limbaugh, who received a cochlear implant in 2001 after going deaf.

With these and other factors at work, a market study by Neurotech Reports predicts sales of neurotechnology products worldwide will more than double from about $3.1 billion in 2006 to $7.6 billion in 2010.

Those rosy growth projections have caught the attention of device makers and suppliers. Venture capital firms are pouring hundreds of millions of dollars into startup neurotech firms. At the same time, medical giants, such as Medtronic, St. Jude and Boston Scientific, are expanding their neurostimulation programs and buying independent companies that have established footholds in specific neurotech niches.

“We see this market as one with very significant growth potential,” says Todd Schneider, medical group VP for AMI Semiconductor, which supplies microprocessors for neurostimulation devices. “Yet the industry is still in its infancy, so the sky’s the limit.”

From Backache to Migraines

Experts agree the biggest current market for neurotechnology is treatment of chronic pain, which affects more than 90 million people in the U.S. alone and costs nearly $80 million a year in lost work time, according to the National Institutes of Health. To get relief, many patients resort to powerful narcotic and analgesic drugs. In one recent year, notes the Dept. of Health and Human Services, overdoses of such drugs accounted for more than 108,000 emergency room visits. Back pain — or the agony from failed back surgery — are the biggest culprits.

Companies like medical giant Medtronic and ANS, which became part of St. Jude Medical in late 2005, have led the way in developing spinal cord stimulation systems (SCS) that act as “pacemakers for pain.” The implantable devices interrupt the pain signals’ pathways to the brain by delivering low-intensity electrical impulses to nerve fibers along the spinal cord. SCS therapy has been shown to reduce pain by 50 percent or more.

The ANS flagship product for chronic pain is the EON™ system, approved by the FDA in June 2005. Its implanted pulse generator (IPG), featuring a rechargeable lithium-ion battery, is designed to last a minimum of seven years at high power settings. EON can also power up to 16 independent electrodes, which gives clinicians more programming options to better manage the patient’s pain.

The key differentiator in the EON is the IPG’s custom microchip and enhanced software, which deliver more speed, power and efficiency versus previous systems, according to Tom Hickman, VP of product management for ANS. The IPG is linked through RF communications to a Rapid Programmer platform, the system’s control unit. This device allows for real-time programming adjustments for patients suffering from complex pain patterns, such as a combination of back and leg pain.

Hickman adds, leads and electrodes also play a key role in neurotech applications and a great deal of intellectual property surrounding these devices involves the number, shape and precise placement of leads and electrodes. “Leads are where the rubber meets the road, in terms of delivering the desired stimulus,” says Hickman. “No amount of programming will overcome poorly placed leads.”

With more than 30,000 patients now getting pain relief through its SCS systems, ANS is exploring other applications. For example, the company is testing its Genesis neurostimulation system in clinical research as a therapy for helping patients with chronic migraine. In this application, the IPG, implanted in the buttock or chest area, sends electrical impulses to the occipital nerves in the back of the head.
Deep Inside the Brain

Beyond chronic pain, engineers and researchers are looking to neurostimulators as a tool for treating brain disorders, such as Parkinson’s disease and to help patients control epilepsy and restore function in the aftermath of strokes.

Medtronic led the way in Deep Brain Stimulation (DBS) with its Activa Therapy, approved by the FDA in 1997, to control movement disorders associated with Parkinson’s and essential tremor. In this application, the electrode array is placed in the thalamus to interrupt wayward brain signals that cause the shaking and abrupt movements that plague these patients.

Some 30,000 patients worldwide have received this therapy since Medtronic commercially launched the Activa device. In most of these cases, drugs had either failed to provide relief from the symptoms or caused serious side effects. Studies also found the device is more effective in controlling movement disorders than a pallidotomy, an ablative surgical procedure that involves removal of brain tissue. Unlike brain surgery, which is not reversible, Activa can be removed if clinicians opt for other treatments.

Among Medtronic’s latest advances in the Activa system is the Kinetra® neurostimulator, approved by the FDA in 2004. This device accommodates two DBS leads carrying electrical impulses to both the left and right sides of brain. Before the Kinetra, treatment of Bilateral symptoms caused by Parkinson’s disease required separate implants of two neurostimulators.

Lynn Otten, the 1999 Design News Engineer of the Year and one of the key Medtronic engineers on the Activa development team, points out the benefits of DBS are by no means limited to patients with movement disorders. “It also holds promise as a treatment for medically refractory epilepsy, as well as severe Depression and obsessive compulsive behavior,” says Otten.

The Brain’s Super Highway

Other firms offer alternative approaches to DBS for treatment of neural disorders. For example, Houston-based Cyberonics owns broad patents giving the company a near monopoly on neurostimulation for epilepsy. Called VNS (vagus nerve stimulation), the therapy features an IPG, roughly the size of a small pocket watch. Implanted in the patient’s left chest area, the device stimulates the left vagus nerve in the neck with a helical-shaped, platinum iridium electrode that wraps around the nerve.

“The advantage of stimulating the Vagus Nerve, which serves as the superhighway to the brain, is that it is easy to access and there is no penetration of neural tissues,” says engineer Reese Terry, the company’s interim CEO. “It is also a relatively easy system to implant and program.” Some 45,000 epilepsy patients have already received VNS therapy and the company is targeting the technology for other conditions, such as severe Depression.

Meanwhile, a fledgling competitor, California-based NeuroPace, is sponsoring an investigational device study of its Responsive Neurostimulator (RNS) System. Implanted in the skull, the RNS is designed to detect abnormal electrical activity in the brain and then deliver electrical stimulation that normalizes brain activity before the patient experiences seizures.

In Seattle, Northstar Neuroscience is also developing an alternative to deep brain surgery for patients recovering from stroke. The company has designed a family of electrodes aimed at stimulating various sectors of the cortex — the outer layer of the brain — that control movement, emotions, hearing, speech and other functions. This year, in its first application, the company hopes to complete pivotal clinical trials for stimulation therapy aimed at improving hand and arm movement in patients recovering from stroke.

In this particular treatment mode, the surgeon will place an array of six electrodes, about the size of a postage stamp, on top of the dura, which is the membrane that covers the brain’s service. This cortical stimulation lead connects to an implantable pulse generator in the chest.

“We saw a number of advantages in focusing on the cortex,” says Northstar COO Jeff Bowers. “First of all, it controls many neurological functions and therefore is a fertile target for intervention. And, as the outer layer of the brain, the cortex is easier for surgeons to access than deeper brain structures.”

Bowers, whose goal is to commercialize the therapy for hand and arm movement by the end of 2008, adds, so far there is no FDA-approved implanted neurostimulator for stroke recovery. But the potential market is great. Some 5 million Americans are stroke survivors, with more than 500,000 new stroke victims surviving each year.
A Litany of Niches

Such examples are just a sampling of the fast-expanding neurotech applications now being developed. Name a malady and there is likely to be a device aimed at treatment.

In Cleveland, NDI Medical has developed what it describes as the market’s smallest multi-channel wireless rechargeable IPG. About the size of a thumb and implanted in the lower abdomen, the device is now being tested in clinical trials as a “bladder pacemaker” to control urinary Incontinence. To achieve its miniaturization goals, NDI turned to Valtronic, a contract manufacturer specializing in microelectronic modules. Valtronic used a circuit assembly technology called 3D chip-scale packaging (3D-CSP). With this process, several flip-chip circuits are assembled on flexible circuit boards, then folded into a compact package. The result: a package 75 percent smaller than conventional assemblies.

“It’s a very exciting time for the neurotechnology industry,” says NDI Medical president Geoffrey Thrope, a biomedical engineer who also was co-inventor of FREEHAND™, an FDA-approved stimulation device to restore hand control to individuals with spinal cord injury. Ten years from now, predicts Thrope, the market for neurotechnology devices could be as high as $20 billion.

Among the applications that could substantially boost that dollar volume are devices for controlling obesity. In the U.S. alone, nearly 15 million people are considered morbidly obese. For such patients, neurostimulation could offer a better and safer alternative to gastric bypass surgery, a procedure with a high risk of mortality and an often lengthy recovery.

EnteroMedics, a privately held Minnesota company with research ties to the Mayo Clinic, has developed a therapy called VBLOC. In this system, a surgeon uses a laparoscope to insert two tiny electrodes next to the vagal nerves just above the junction between the esophagus and the stomach. An implanted neuroregulator, linked to the electrodes, produces low-energy, high-frequency electrical impulses to block the vagal nerve signals responsible for such functions as expansion of the stomach as food enters.

The company is already conducting clinical trials of VBLOC at several sites around the world and is seeking an Investigational Device Exemption from the FDA in advance of planned clinical trials in the U.S. this year, according to CEO Mark Knudson.

Only the Beginning

Looking to the future, neurotechnology will be tackling even tougher challenges. In Massachusetts, Cyberkinetics hopes to receive a Humanitarian Device Exemption this year from the FDA for a patented neuromodulation device designed to promote nerve fiber Regeneration in individuals who have suffered spinal cord injury. Called Andara, the system features a battery-powered oscillating field stimulator (OFS) about the size of a lipstick tube with six leads. Three of the leads are attached to the bone at a distance of two disk segments above the injury and the other three are attached at a similar distance below the injury. The device stimulates the neural fibers that surround the spinal cord to grow across the injury to restore some sensory and Motor function.

Cyberkinetics is also involved in clinical trials with another system, the BrainGate Neural interface, which uses a sensor implanted on the motor cortex of the brain and an exterior device that analyzes brain signals. The system is designed to allow motor-impaired individuals, such as those with spinal cord injury or ALS, to control a computer, wheelchair or other devices with their thoughts. Together with engineers from the Cleveland FES Center, the company is also conducting longer-term research to investigate whether a BrainGate-type system could be used to control an implanted neurostimulator for moving a paralyzed patient’s hands or arms.

The Cleveland FES Center, headed by past Design News’ Engineer of the Year Hunter Peckham, is itself pushing the envelope of neurotechnology through work on a “networked neural Prosthesis.” In such a system, a single stimulator implanted in the chest would allow a paralyzed individual to control several different functions, such as hand movements, standing and bladder function.

“One thing that you can’t argue about,” says Peckham, “is that the neurotechnology field is very hot. And it’s an area where American companies enjoy a very strong position.”

Adds John Donoghue, chief scientific officer of Cyberkinetics, “This field has extraordinary potential. We’re just at the beginning of seeing a whole range of new diagnostic, restorative and therapeutic devices.”

Lawrence D. Maloney, Contributing Editor — 5/14/2007

The Power Behind the Pulses

Neurostimulators have not yet reached the sophistication of the latest pacemaker-defibrillator devices, whose closed-loop systems sense electrical activity in a patient’s heart and respond as needed with appropriate electrical impulses to restore normal function. In contrast, technicians or medical personnel program neurostimulators, adjusting such parameters as frequency and amplitude of pulses based on what they have learned from observing past patients in clinical and research settings.

Even so, the latest neurostimulators, like most other electronic devices, feature microprocessors that offer ever more functionality in tinier packages. Integration of such features as MEMs sensors is also on the horizon.

Some device makers design their own custom integrated circuits to control the implanted pulse generators. Others rely on chip manufacturers, such as X-FAB, STMicroelectronics and AMI Semiconductor. Many IC makers, however, still avoid medical implants because of concerns over product liability issues.

“The quality demands that are put on you as a supplier in medical applications are very significant,” says Todd Schneider, vice president of AMI’s Medical Group, “but we are used to that as a major supplier to the auto industry.” Northstar Neuroscience, for example, is working with AMI in the design and manufacture of an application specific integrated circuit for its Stroke Recovery System (see main story).

The ASICs used in implanted pulse generators (IPGs) typically combine analog and digital signals on a single chip and are designed to consume as little energy as possible to extend the life of the rechargeable lithium-ion batteries that power most IPGs. Stimulus output is typically in the 10- to 20-V range for neurostimulation applications.

The latest IPGs also integrate RF communications, featuring ultra-low-power wireless chips designed to operate within the 402-405 MHz band of frequencies that the FCC has assigned to MICS (medical implant communications service). AMI Semiconductor, for instance, offers a standard wireless transceiver for this application, called the 53000, as well as a less complex chip, the 52100, for even lower power use. Wireless communication allows technicians, using an exterior controller, to program the IPG, as well as recharge the implant’s batteries. Data collected by the implant can also be wirelessly transmitted to the outside world for review by medical specialists.

Moving forward, Schneider of AMI expects future chips for implants will incorporate A-to-D converters for closed-loop operation, as well as digital signal processing for more accurate and flexible control. Others, such as James Cavuoto, editor/publisher of Neurotech Reports, believe next-generation devices will also integrate sensor channels that will allow stimulus therapy to be modified in real time for maximum patient benefit.